Is Chemoimmunotherapy for Upfront CLL on Life Support?

For years, standard of care first-line treatment for chronic lymphocytic leukemia (CLL) included the FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy regimen. However, the past decade has brought tremendous innovation in the treatment of CLL. With seven new drug approvals in the past 5 years alone, patients with CLL now have more options then ever – as do the hematologists who treat them.

This dilemma was the subject of a debate session at the 2019 ASH Annual Meeting, where two leading CLL experts discussed whether the old standby FCR regimen still has a role in upfront treatment of patients with CLL, or whether clinicians should “pull the plug” on chemoimmunotherapy.

Susan M. O’Brien, MD, Associate Director for Clinical Science at the Chao Family Comprehensive Cancer Center at the University of California, Irvine, and Stephan Stilgenbauer, MD, Deputy Chair of the Department of Internal Medicine at the University of Ulm in Germany, tackled this question through a discussion of several patient scenarios, supporting their viewpoints with data on the use of novel treatments such as ibrutinib and venetoclax.

Case #1: Previously Untreated CLL

To start the discussion, Drs. O’Brien and Stilgenbauer were presented with the following scenario: A patient was diagnosed with CLL at age 57 and was followed with watchful waiting. After 5 years, the patient, now 62, has a white blood cell count of 102,000/µL, an absolute neutrophil count of 1,000, a platelet count of 90×109/L, and hemoglobin level of 10.4 g/dL. The patient had a 4 cm right axillary node, 3 cm left axillary node, bilateral 2 cm cervical nodes, and palpable spleen. Serum chemistry was normal.

With no change in the patient’s FISH or TP53 status, Dr. O’Brien opted to treat with FCR, based on results from a randomized phase III trial published by Shanafelt et al. in The New England Journal of Medicine in 2019.1 Patients with previously untreated CLL who were ≤70 years were randomized 2:1 to receive either ibrutinib + rituximab for 6 cycles followed by ibrutinib alone until progression, or 6 cycles of FCR. Patients with del17p were excluded.

While ibrutinib + rituximab was associated with significantly higher rates of 3-year progression-free survival (PFS; 89.4% vs. 72.9%; hazard ratio [HR] = 0.35; 95% CI 0.22-0.56; p<0.001) and 3-year overall survival (OS; 98.8% vs. 91.5%; HR=0.17; 95% CI 0.05-0.54; p<0.001) in the overall population, Dr. O’Brien noted that “[the subset of] IGHV-unmutated patients is really where we see all of the benefit.” In a subgroup analysis of patients with and without IGHV-mutated disease, those without the mutation had a 3-year PFS of 90.7% with ibrutinib + rituximab, compared with 62.5% with FCR (HR=0.26; 95% CI 0.14-0.50). However, in those with the IGHV mutation, the 3-year PFS rates were similar between arms: 87.7% for ibrutinib + rituximab versus 88.0% for FCR (HR=0.44; 95% CI 0.14-1.36).

“This is not that surprising, because we know that patients with an unmutated immunoglobulin gene have much shorter PFS with any chemotherapy that you give them [compared with those with mutated IGHV],” Dr. O’Brien said. “The relevant point is that, so far, we don’t have any difference based on mutation status.”

In response, Dr. Stilgenbauer noted that this trial was not powered for retrospective subgroup analysis based on IGHV status. “Patients with mutated IGHV status derived benefit from ibrutinib + rituximab over FCR simply based on group size,” he said. “More important, there was a difference in OS. It was a 2:1 randomization, therefore, it is not 4 deaths versus 10 deaths, but 4 deaths with ibrutinib versus 20 with FCR, or a 1% versus 6% death rate within a relatively short follow-up time. To me, this is the key argument that ibrutinib + rituximab or ibrutinib alone is the better treatment.”

Along with efficacy, tolerability is a crucial component of treatment consideration, Dr. Stilgenbauer added. Given available evidence, novel agents are preferable over standard chemoimmunotherapies.

“Of note, even in young CLL patients fit to withstand FCR, [rates of] neutropenia, anemia, and thrombocytopenia are several-fold higher with FCR treatment,” he said. He added that “[incidence of] infection and neutropenic fever were much higher.”

In response to the argument that clinicians may give ibrutinib + rituximab to avoid dealing with myelosuppression, Dr. O’Brien said she still supported use of FCR because she is “very swayed by the long-term data.” These include three studies demonstrating plateaus in PFS curves among pa-tients with IGHV-mutated CLL treated with FCR.2,3,4 One of these studies, from MD Anderson Cancer Center, has the longest follow-up of patients with the IGHV mutation treated with firstline FCR.5

“If patients had mutated disease, that plateau at about 11 to 16 years is out at about 60%,” Dr. O’Brien said. “If the patient experiences minimal residual disease negativity, that plateau rises to 80%. I firmly believe that there is a cure fraction there.”

In his rebuttal, Dr. Stilgenbauer again pointed to limitations in the research, noting that the MD Anderson study was a single-arm, single-center trial done at a highly specialized center. “That plateau is beyond the median follow-up, so it is statistically invalid,” he said.

Case #2: An Older Patient With CLL

Next, Drs. O’Brien and Stilgenbauer discussed the treatment of an older patient diagnosed with IGHV-mutated CLL. The 74-year-old patient had normal FISH results and had good performance status, renal function, and liver function.

In this situation, Dr. O’Brien said she would opt against chemotherapy, supported by data from two trials. First, the iLLUMINATE trial showed that ibrutinib + obinutuzumab led to longer median PFS, compared with chlorambucil + obinutuzumab (not reached vs. 19.0 months; HR=0.23; 95% CI 0.15-0.37; p<0.0001).5

“In a high-risk population, defined as patients with del17p, TP53 mutation, or del11q, [the benefit was] even more marked because those features are predictive of worse outcomes with chemotherapy,” Dr. O’Brien said.

For many patients, data from the ALLIANCE A041202 trial may be more relevant, she noted. The A041202 trial randomized untreated patients ≥65 years to bendamustine + rituximab (BR), ibrutinib + rituximab, or ibrutinib alone.6 A greater percentage of patients assigned to the two ibrutinib regimens were progression-free at 2 years (88% and 87%, compared with those who were treated with BR (74%).

“If you look at patients with IGHV-mutated disease, we see this same trend,” she added.

As expected, patients assigned to BR had greater rates of myelosuppression, while those assigned to an ibrutinib-containing arm had higher rates of atrial fibrillation and hypertension.

Ultimately, the decision comes down to the treating hematologist’s judgment on whether it is appropriate to treat a healthy, fit, 74-year-old patient with BR. “Personally I never use BR, as there is no plateau on the curve,” Dr. O’Brien said. “The main reason I’m still interested in FCR is because I do think there is a cure fraction. If there is no cure fraction with BR, I would rather give the regimen that doesn’t have myelosuppression.”

Dr. Stilgenbauer further supported the role of novel therapies in the treatment of this older patient, citing data on acalabrutinib, a recently FDA-approved, second-generation Bruton tyrosine kinase inhibitor. In the ELEVATE TN study, treatment-naïve patients were randomly assigned 1:1:1 to acalabrutinib alone, acalabrutinib + obinutuzumab, or obinutuzumab + chlorambucil.7 Patients in both acalabrutinib arms had significantly higher PFS rates (HR=0.10 with acalabrutinib alone and HR=0.20 with acalabrutinib + obinutuzumab; p<0.0001 for both comparisons). Subgroup analyses also revealed that patients with IGHV-mutated disease derived greater benefit from acalabrutinib therapy than chlorambucil-based therapy.

The OS results were particularly impressive, he added. “Despite the opportunity for patients to cross over, researchers observed at least a trend in favor of a survival advantage with novel therapy compared with chemotherapy,” he explained. The findings suggest that, “not only for young patients, but for the vast majority of elderly patients, it is better to have a chemotherapy-free option in the frontline setting.”

The CLL14 trial, which tested chlorambucil + obinutuzumab against venetoclax + obinutuzumab in previously untreated older patients or those considered unfit for standard chemoimmunotherapy, also supported use of a chemotherapy-free option in this population.8 The novel therapy combination led to a significant improvement in PFS, compared with the chlorambucil-based regimen (88.2% vs. 64.1%). The survival benefit was seen in patients with or without mutated disease.

Adverse events were balanced between the treatment arms, Dr. Stilgenbauer noted. Patients treated with the venetoclax combination had slightly more neutropenia, but this did not translate into more infections.

Case #3: CLL With Del17p

Finally, both CLL experts revisited the original patient scenario to discuss how their treatment approach would change if the patient had been found to have del17p.

“Until recently, there was a simple straightforward answer to this question – ibrutinib – because these patients [have poor responses] to chemotherapy,” Dr. O’Brien said. “Del17p is such a poor prognostic factor that it renders mutation status irrelevant.”

For example, in the CLL8 trial, which compared FCR with fludarabine + cyclophosphamide, patients with del17p had far worse survival than the overall population, whether they had IGHV-mutated disease or not. “The median survival was about 1 year, so these patients had very poor survival with FCR – arguably the best chemotherapy that we have.”

Dr. O’Brien noted that, thankfully, del17p incidence is quite low in upfront treatment of CLL. Still, that also makes it difficult to collect data on treatment. In data reported by the National Institutes of Health, older patients with CLL with del17p or TP53 mutation had 5-year PFS rates of approximately 80%.9

“Not only is this better than with chemoimmunotherapy, it is multiple logs better than chemoimmunotherapy,” Dr. O’Brien said. “Although this is still a high-risk population, [their prognosis] looks a lot more favorable in a frontline setting [with ibrutinib].”

Dr. Stilgenbauer agreed that chemoimmunotherapy is not an option in patients with del17p, again citing data from the CLL14 trial and the availability of other, non-ibrutinib options for these patients. In patients with del17p or TP53 mutation, venetoclax + obinutuzumab improved PFS outcomes, compared with chlorambucil + obinutuzumab. In addition, the longer treatment-free interval after use of the novel combination allows for potential re-treatment with venetoclax-based therapy.

“This leaves the ibrutinib option in [a clinician’s] back pocket,” Dr. Stilgenbauer added. “We have more options for patients with del17p and no clear-cut evidence about which non-chemoimmunotherapy agent – either ibrutinib or venetoclax – should be the preferred option in the frontline setting.”

Both panelists agreed that, given the increased number of options available, including targeted therapy, this is an exciting time in the management of CLL. Several unresolved issues remain though, not least of which is the need to address the high costs of novel agents. —By Leah Lawrence


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